P1017: HARBOR: A PHASE 2/3 STUDY OF BLU-263 IN PATIENTS WITH INDOLENT SYSTEMIC MASTOCYTOSIS AND MONOCLONAL MAST CELL ACTIVATION SYNDROME
Authors: M. Castells, R. Scherber, V. Bhavsar, K. He, C. Akin
Journal: HemaSphere (2022)

Background: The KIT D816V mutation plays a key role in the aggregation and accumulation of aberrant mast cells which characterize systemic mastocytosis (SM), a rare, clonal mast cell neoplasm. The disease subtype of indolent SM (ISM) is characterized by the presence of mast cell aggregates in bone marrow and other organs which can lead to chronic, debilitating, and potentially life-threatening symptoms. Mast cell infiltration in the skin is common in ISM but is not always present. Similarly, monoclonal mast cell activation syndrome (mMCAS) is a clonal KIT D816V–positive mast cell disease without mast cell aggregates which can be accompanied by similar symptoms. Neither ISM nor mMCAS currently have approved molecularly targeted therapies, and significant symptom burden exists despite best supportive care (BSC) symptom-based therapy. BLU-263 is a novel, oral, next-generation tyrosine kinase inhibitor, exhibiting potent inhibition of KIT D816V and an evolved preclinical profile with limited central nervous system penetration. In our phase 1 study in normal healthy volunteers, BLU-263 was safe, with linear pharmacokinetics across all tested doses and a half-life allowing once-daily dosing, and thus supporting continued development for patients with SM. Aims: HARBOR (NCT04910685) is a randomized, double-blind, placebo-controlled, phase 2/3 study assessing efficacy and safety of orally administered BLU-263 in patients with ISM whose symptoms are not adequately controlled by standard therapies. Methods: Part 1 of the study includes 3 dose groups (25 mg, 50 mg, and 100 mg) and a placebo group combined with BSC therapies to determine the recommended dose (RD) of BLU-263 in approximately 40 patients with ISM (Figure). After determination of the RD and analysis of Part 1, Part 2 will open for enrollment of approximately 303 patients undergoing BSC therapies, randomized 2:1 to BLU-263 or placebo. The primary endpoint of Part 2 is the proportion of patients achieving a ≥30% reduction in total symptom score as assessed by the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF). Patients completing Part 1 or Part 2 will roll over to Part 3 for open-label long-term evaluation of BLU-263 at the RD. The exploratory, open-label study Part M will explore BLU-263 at the RD in patients diagnosed with mMCAS. Other endpoints including but not limited to Mastocytosis Quality of Life scores, KIT D816V allele burden, and bone marrow mast cell involvement will also be assessed. Two pharmacokinetic (PK) groups will enroll patients with ISM prior to or concurrent with the Part 1 and Part 2 study cohorts to better characterize the PK and safety of BLU-263 in specific patient populations. Results: Topline results of Part 1 of the study are anticipated in the second half of 2022. Image:Summary/Conclusion: Overall, the goal of HARBOR is to investigate the safety and efficacy of the selective, targeted KIT inhibitor BLU-263 as a potential treatment option to reduce symptom burden for patients with ISM.